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Sarcomas, malignant tumors from mesenchymal tissues, exhibit poor prognosis despite advancements in treatment modalities such as surgery, radiotherapy, and chemotherapy, with doxorubicin being a cornerstone treatment. Resistance to doxorubicin remains a significant hurdle in therapy optimization. This study aims to dissect the molecular bases of doxorubicin resistance in sarcoma cell lines, which could guide the development of tailored therapeutic strategies. Eighteen sarcoma cell lines from 14 patients were established under ethical approvals and classified into seven subtypes. Molecular, genomic, and transcriptomic analyses included whole-exome sequencing, RNA sequencing, drug sensitivity assays, and pathway enrichment studies to elucidate the resistance mechanisms. Variability in doxorubicin sensitivity was linked to specific genetic alterations, including mutations in TP53 and variations in the copy number of genomic loci like 11q24.2. Transcriptomic profiling divided cell lines into clusters by karyotype complexity, influencing drug responses. Additionally, pathway analyses highlighted the role of signaling pathways like WNT/BETA-CATENIN and HEDGEHOG in doxorubicin-resistant lines. Comprehensive molecular profiling of sarcoma cell lines has revealed complex interplays of genetic and transcriptomic factors dictating doxorubicin resistance, underscoring the need for personalized medicine approaches in sarcoma treatment. Further investigations into these resistance mechanisms could facilitate the development of more effective, customized therapy regimens.

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Adenosquamous carcinoma of the pancreas (ASCP) is a rare and aggressive variant of pancreatic cancer, characterized by both adenocarcinoma and squamous cell carcinoma components. It presents significant diagnostic and therapeutic challenges due to its atypical histology and poor prognosis. A 72-year-old male presented with abdominal pain, lighter-colored stools, and intermittent nausea. Initial imaging revealed a complex mass in the distal pancreatic body and tail. Elevated lipase levels and subsequent endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) suggested an atypical pancreatic lesion with keratinizing squamous cells. Further investigation through fiberoptic bronchoscopy and EBUS-guided transbronchial needle aspiration (TBNA) confirmed carcinoma with squamous differentiation. Genetic testing identified KRAS G12D and PIK3CA mutations. The multidisciplinary tumor board recommended systemic chemotherapy with mFOLFIRINOX and G-CSF support. The patient underwent twelve cycles of mFOLFIRINOX with dose adjustments for thrombocytopenia and effective management of chemotherapy-related side effects. Restaging CT scans showed a decrease in tumor size and stable metastatic nodes. The patient showed a partial biochemical response with decreasing CA 19-9 levels and disease stabilization on imaging. This case demonstrates the critical role of a multidisciplinary approach in managing rare pancreatic malignancies. ASCP requires a comprehensive diagnostic and therapeutic strategy involving advanced imaging, histopathological confirmation, and personalized chemotherapy. Integrating advanced diagnostic techniques, molecular profiling, and a multidisciplinary approach is essential for improving patient outcomes and providing comprehensive care for this challenging malignancy. Addressing the psychological aspects and offering compassionate care are vital for supporting patients through their treatment journey.

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BACKGROUND: Next-generation sequencing (NGS) has become widely available but molecular profiling-guided therapy (MGT) had not been well established in the real world due to lack of available therapies and expertise to match treatment. Our study was designed to test the feasibility of a nationwide platform of NGS-guided MGT recommended by a central molecular tumor board (cMTB) for metastatic solid tumors. PATIENTS AND METHODS: Patients with advanced or metastatic solid tumors with available NGS results and without standard treatment were enrolled. The cMTB interpreted the patients' NGS reports and recommended the following: (i) investigational medicinal products (IMPs) approved in other indications; (ii) alternative treatments; (iii) clinical trials. The primary variables were the proportion of patients with actionable genomic alterations and those receiving MGT as per cMTB recommendations. Others included treatment duration (TD), overall response rate (ORR), disease control rate (DCR), and safety. RESULTS: From February 2021 to February 2022, 193 cases [99 (51.3%) men; median age 58 years (range 24-88 years); median line of previous treatment 3 (range 0-9)] from 29 sites were enrolled for 60 cMTB sessions. The median time from case submission to cMTB discussion was 7 days (range 2-20 days), and to IMP treatment initiation was 28 days (range 14-90 days). Actionable genetic alterations were found in 145 patients (75.1%). A total of 89 (46.1%) patients received actual dosing of IMPs, and 10 (5.2%) were enrolled in cMTB-recommended clinical trials, achieving an MGT rate of 51.3%. ORR and DCR of IMPs were 10.1% and 72.5%, respectively. The median TD was 3.5 months [95% confidence interval (CI) 2.8-5.5 months], and the 4-month TD rate was 44.9%. The median overall survival of patients who received IMPs was 6.9 months (95% CI 5.2-10.0 months). CONCLUSION: KOSMOS confirmed the feasibility of MGT recommended by the cMTB, achieving a high MGT match rate and promising effectiveness in heavily pretreated advanced cancer patients.

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Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer-associated mortality, with a rising global incidence. A paucity of strong predictive risk factors mean screening programmes are difficult to implement. Historically, a lack of identifiable and actionable driver mutations, coupled with a relatively immunosuppressed tumour microenvironment, has led to a reliance on cytotoxic chemotherapy. The NAPOLI-3 trial has reported data supporting consideration of NALIRIFOX as a new first-line standard of care. Kirsten Rat Sarcoma Virus (KRAS) G12D mutations are present in >90% of all PDAC's; exciting breakthroughs in small molecule inhibitors targeting KRAS G12D may open new modalities of treatment, and therapies targeting multiple KRAS mutations are also in early clinical trials. Although immunotherapy strategies to date have been disappointing, combination with chemotherapy and/or small molecule inhibitors hold promise and warrant further exploration.

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Meningiomas are the most common primary intracranial tumors in adults and typically have a slow-growing and benign nature. However, there is also a substantial subset of meningiomas that shows aggressive clinical behavior and is refractory to standard treatment modalities, which are still limited to surgery and/or radiotherapy. Despite intensive research, no systemic treatment options are yet available in the clinic for these challenging tumors, resulting in poor patient outcome. Intensive research on the molecular pathogenesis of meningiomas has led to improved diagnostic tools, but so far there is no standardized implementation for the molecular profiling of these tumors for clinical practice. Recent research advances have also focused on the immunophenotyping of meningiomas, leading to several clinical trials examining the use of immune checkpoint blockade therapy in patients with clinically aggressive subtypes. In this review, we aim to summarize the current knowledge on the molecular and immunological landscape of meningiomas in detail and provide current and progressive ideas for future directions.

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Breast cancer (BC) remains the most prevalent cancer among women and the leading cause of cancer-related mortality worldwide. The heterogeneity of BC in terms of histopathological features, genetic polymorphisms, and response to therapies necessitates a personalized approach to treatment. This review focuses on the impact of molecular profiling on therapy management in breast cancer, emphasizing recent advancements in next-generation sequencing (NGS) and liquid biopsies. These technologies enable the identification of specific molecular subtypes and the detection of blood-based biomarkers such as circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), and tumor-educated platelets (TEPs). The integration of molecular profiling with traditional clinical and pathological data allows for more tailored and effective treatment strategies, improving patient outcomes. This review also discusses the current challenges and prospects of implementing personalized cancer therapy, highlighting the potential of molecular profiling to revolutionize BC management through more precise prognostic and therapeutic interventions.

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Introduction: Therapeutic decisions in early breast cancer are based on clinico-pathological features which are subject to intra- and inter-observer variability. This single-center decision impact study aimed to evaluate the effects of the Prosigna assay on physicians' adjuvant treatment choices. Methods: Between 09/2017 and 02/2018, formalin-fixed tumor samples from 52 newly diagnosed, postmenopausal, hormone receptor-positive, HER2-negative breast cancer (T1-T2; pN0-N1a) patients were analyzed. Pre-test clinical judgements and Prosigna test results were compared. Results: The mean age was 59 (42-77). Invasive ductal carcinoma (79.2%), grade 2 (52.8%) and T1c-N0 tumors (43.4%) were represented. There was 40.4% discordance between the pre- and post-test risk of recurrences. No significant change was observed in the clinical intermediate risk category, while there was a net reclassification of low-risk patients into a high Prosigna recurrence risk group. In addition, clinically determined intrinsic subtypes were 34.6% discordant with the Prosigna results, which is largely driven by the reclassification of the luminal A tumors into the Prosigna-assessed luminal B group. Before the Prosigna test, endocrine treatment was the primary choice in 20 patients (39.2%), and chemotherapy was recommended to 31 patients (60.8%). Overall, the Prosigna assay led to a change in treatment choice for one patient. Conclusions: Although conventional risk assessment methods are relatively inexpensive with shorter turnaround times, their accuracy and value for risk reduction are suboptimal. According to our results, the Prosigna assay was found to be a relevant tool for the clinical decision making process. Long-term follow-up of these patients will elucidate the potential benefits of using multigene molecular tests as biomarkers for treatment.

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Infectious diseases, driven by a diverse array of pathogens, can swiftly undermine public health systems. Accurate diagnosis and treatment of infectious diseases-centered around the identification of biomarkers and the elucidation of disease mechanisms-are in dire need of more versatile and practical analytical approaches. Mass spectrometry (MS)-based molecular profiling methods can deliver a wealth of information on a range of functional molecules, including nucleic acids, proteins, and metabolites. While MS-driven omics analyses can yield vast datasets, the sheer complexity and multi-dimensionality of MS data can significantly hinder the identification and characterization of functional molecules within specific biological processes and events. Artificial intelligence (AI) emerges as a potent complementary tool that can substantially enhance the processing and interpretation of MS data. AI applications in this context lead to the reduction of spurious signals, the improvement of precision, the creation of standardized analytical frameworks, and the increase of data integration efficiency. This critical review emphasizes the pivotal roles of MS based omics strategies in the discovery of biomarkers and the clarification of infectious diseases. Additionally, the review underscores the transformative ability of AI techniques to enhance the utility of MS-based molecular profiling in the field of infectious diseases by refining the quality and practicality of data produced from omics analyses. In conclusion, we advocate for a forward-looking strategy that integrates AI with MS-based molecular profiling. This integration aims to transform the analytical landscape and the performance of biological molecule characterization, potentially down to the single-cell level. Such advancements are anticipated to propel the development of AI-driven predictive models, thus improving the monitoring of diagnostics and therapeutic discovery for the ongoing challenge related to infectious diseases.

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BACKGROUND: The association between the molecular profiles and prognosis of Stage II colorectal cancer remains unclear. This study aimed to examine the risk factors for relapse of Stage II colorectal cancer using molecular profiling. METHODS: We retrospectively enrolled patients with pStage II colorectal cancer who did not receive perioperative adjuvant therapy and whose surgically resected specimens were evaluated using gene expression and whole-exome analyses between January 2014 and December 2018. We evaluated the long-term outcomes and examined the risk factors for relapse-free survival. RESULTS: We evaluated 322 patients with pStage II colorectal cancer, including 126 (39.1%) with right colon cancer. Eighty-seven patients (27.0%) had pT4 tumor, 175 (54.3%) had positive venous invasion, 120 (37.3%) had positive lymphatic invasion, and 68 (21.1%) had perineural invasion. The presence of mutations in key genes for colorectal cancer development based on whole-exome analyses was as follows: APC, 245 (76.1%); TP53, 208 (64.6%); and KRAS, 134 (41.6%). According to the consensus molecular subtype classification based on gene expression, 76 patients (23.6%) had consensus molecular subtype 4 and a significantly lower relapse-free survival than the other patients (5-year relapse-free survival: 83.8% vs. 92.9%, p = 0.017). Perineural invasion (hazard ratio: 5.316, p < 0.001) and consensus molecular subtype 4 (hazard ratio: 2.399, p = 0.020) were identified as independent risk factors for relapse-free survival. CONCLUSIONS: Molecular profiling of Stage II colorectal cancer to assess the risk factors for relapse may contribute to the indication and drug selection for adjuvant chemotherapy.

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Background: Since the seminal publication of the TCGA consortium in 2013, the molecular classification of endometrial cancer has been widely accepted as a new and powerful tool to better understand the natural history of this malignancy. Adoption of routine molecular classification around the world has been limited. We sought to demonstrate our initial experience in incorporating the four molecular subtypes for endometrioid carcinomas. Methods: This was a retrospective analysis at a single center in Portugal. Molecular classification was determined using immunohistochemical staining for MMR and p53 and Sanger Sequencing to determine POLE mutation status as per published PROMISE method. Descriptive statistics were reported. Results: 20 patients with endometrioid histology were included. Median age of the cohort was 64 years (range 45-76). Median Body Mass Index (kg/m2) was 29.81 (range 21.3-43.1). In terms of tumor grading, 16 (80%) of the endometrial carcinomas of the cohort were low-grade (either grade 1 or grade 2). 16 (80%) of the cases were FIGO stage I. Regarding the molecular classification the tumors were classified as: MMRd [n = 6 (30%)]; p53 abn [n = 2 (10%)]; NSMP (n = 10 (50%)), POLE ultramut [n = 2 (10%)]. Conclusion: Despite the small sample size, we were able to show that molecular classification is feasible. To our knowledge this is the first cohort of endometroid endometrial carcinomas fully characterized according to the TCGA classification in Portugal, from one single center.

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Colorectal cancer that occurs before age of 50 is defined as Early-Onset Colorectal Cancer (EOCRC). Its incidence has worryingly increased since the late 90 s and is expected to keep rising in the next future, despite Late-Onset CRC (LOCRC) is decreasing worldwide. Because of this, there is an urgent need to better understand this subset of patients in order to give them the best treatment possible. However, most of the literature is retrospective and often discordant. In this review, we aim to provide a general overview of the issue, endeavoring to highlight the current available knowledge. We decided to move from the beginning, investigating risk factors and inheritance, passing through diagnosis and clinical aspects, and to conclude with the translational part, focusing on the biology of the tumor. However, lot of questions remain open, including screening age and prognosis. Indeed, young patients tend to be treated more aggressively, even if a survival benefit has not been proven yet. Every clinician should be aware of the best practice for young people, and more translational studies are awaited in order to clarify is EOCRC represents a distinct biological entity.

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Multiple myeloma, a complex hematologic malignancy, has devastating consequences for patients, including dramatic bone loss, severe bone pain, and pathological fractures that markedly decrease the quality of life and impact the survival of affected patients. This necessitates a refined understanding of biomarkers for accurate diagnosis and prognosis of such severe malignancy. Therefore, this article comprehensively covers current research, elucidating the diverse spectrum of biomarkers employed in clinical settings. From traditional serum markers to advanced molecular profiling techniques, the review provides a thorough examination of their utility and limitations. Through this scoping review, emphasis is placed on the evolving landscape of personalized medicine, where biomarkers play a pivotal role in tailoring therapeutic strategies. The integration of genomic, proteomic, next generation sequencing and flow cytometric data further enriches the discussion, unravelling the molecular intricacies underlying disease progression. The updated criteria allow for the treatment of people who clearly would benefit from therapy and might live longer if treated before significant organ damage occurs. Navigating through the evolving diagnostic and prognostic paradigms in multiple myeloma, this article equips clinicians and researchers with crucial insights for optimizing patient care and advancing future therapeutic approaches.

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INTRODUCTION: Molecular profiling has become essential in the management of patients with biliary tract cancer (BTC). The aim of this study was to evaluate the practices of French genetics platforms in the management of BTCs. METHODS: A survey was developed by a multidisciplinary group and distributed to each of the 28 French genetics platforms over a one-month period. RESULTS: Twenty-one platforms answered the survey (75%). A majority (62%) had performed more than 50 analyses for BTCs over the last two years, with an average turnaround time for results evaluated between 11 and 15 days for 62% of them. Three quarters (76%) of the platforms performed both DNA and RNA analysis, while a quarter (24%) performed RNA analysis only. A commercial panel was used by 50% of platforms for DNA analysis, and 80% for RNA. Panels included between 10 and 50 genes for 76% of platforms. All responding platforms systematically tested for IDH1 mutations, FGFR2 fusions and BRAF mutations. A majority systematically tested for HER2 amplification, MSI status and TP53 mutation (88%, 81% and 69% respectively). DISCUSSION: This national survey of French genetics platforms shows good performance and compliance with recommendations for molecular analysis. However, many medical, financial and organizational obstacles remain upstream of these platforms.

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Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event. Case presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma. Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile.

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BACKGROUND: Young women with breast cancer (YWBC; ≤40 years) often have a poorer prognosis than older women with breast cancer (OWBC; ≥65 years). We explored molecular features of tumors from YWBC and OWBC to identify a biologic connection for these patterns. MATERIALS AND METHODS: We retrospectively analyzed the molecular profiles of 1879 breast tumors. Testing included immunohistochemistry (IHC), in situ hybridization (ISH), and next-generation sequencing. Statistical analyses included Pearson's chi2 test for comparisons, with significance defined as FDR (false discovery rate)-P < .05. RESULTS: TP53 and BRCA1 somatic mutations were more common in YWBC tumors than in OWBC tumors (53%, 42%; P = .0001, FDR-P = .0025 and 7%, 2%; P = .0001, FDR-P = .0025; respectively). Conversely, OWBC tumors had higher androgen receptor expression (55%, 45%; P = .0002, FDR-P = .0025) higher PD-L1 expression detected by IHC (8%, 5%; P = .0476, FDR-P = .2754), and more frequent PIK3CA mutations (33%, 17%; P = < .0001, FDR-P = < .0001). Among HR+/HER2- samples, YWBC had more gene amplifications in FGF3 (27%, 10%; P = .0353, FDR-P = .2462), FGF4 (27%, 9%; P = .0218, FDR-P = .1668), FGF19 (30%, 12%; P = .034, FDR-P = .2462) and CCND1 (37%, 18%; P = .0344, FDR-P = .2462) than OWBC. CONCLUSIONS: Our data suggest distinct molecular aberrations exist between YWBC and OWBC. Exploiting these molecular changes could refine our treatment strategies in YWBC and OWBC.

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The rapid development of molecular medicine has opened up new perspectives for the diagnosis and treatment of urological tumors. Urology faces the challenge of effectively treating advanced cancer, especially in view of the genetic diversity of urological tumors. The molecular tumor board offers an innovative approach to identify targeted therapy options based on the individual genetic signatures of tumor cells or tumor microenvironment-based treatment options. In this article, the concept of the molecular tumor board in urology is presented using the example of prostate cancer. We discuss the principles, applications, and future prospects of this promising approach.

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(1) Background: Pancreatic ductal adenocarcinoma (PDAC) has low survival rates despite treatment advancements. Aim: This study aims to show how molecular profiling could possibly guide personalized treatment strategies, which may help improve survival outcomes in patients with PDAC. (2) Materials and Methods: A retrospective analysis of 142 PDAC patients from a single academic center was conducted. Patients underwent chemotherapy and next-generation sequencing for molecular profiling. Key oncogenic pathways were identified using the Reactome pathway database. Survival analysis was performed using Kaplan-Meier curves and Cox Proportional Hazards Regression. (3) Results: Patients mainly received FOLFIRINOX (n = 62) or gemcitabine nab-paclitaxel (n = 62) as initial chemotherapy. The median OS was 13.6 months. Longer median OS was noted in patients with NOTCH (15 vs. 12.3 months, p = 0.007) and KIT pathway mutations (21.3 vs. 12.12 months, p = 0.04). Combinatorial pathway analysis indicated potential synergistic effects on survival. In the PFS, PI3K pathway (6.6 vs. 5.7 months, p = 0.03) and KIT pathway (10.3 vs. 6.2 months, p = 0.03) mutations correlated with improved PFS within the gemcitabine nab-paclitaxel subgroup. (4) Conclusions: Molecular profiling could play a role in PDAC for predicting outcomes and responses to therapies like FOLFIRINOX and gemcitabine nab-paclitaxel. Integrating genomic data into clinical decision-making can benefit PDAC treatment, though further validation is needed to fully utilize precision oncology in PDAC management.

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PURPOSE OF REVIEW: Pediatric low-grade gliomas (pLGGs) often result in significant long-term morbidities despite high overall survival rates. This review aims to consolidate the current understanding of pLGG biology and molecular features and provide an overview of current and emerging treatment strategies. RECENT FINDINGS: Surgical resection remains a primary treatment modality, supplemented by chemotherapy and radiotherapy in specific cases. However, recent advances have elucidated the molecular underpinnings of pLGGs, revealing key genetic abnormalities such as BRAF fusions and mutations and the involvement of the RAS/MAPK and mTOR pathways. Novel targeted therapies, including MEK, BRAF and pan-RAF inhibitors, have shown promise in clinical trials, demonstrating significant efficacy and manageable toxicity. Understanding of pLGGs has significantly improved, leading to more personalized treatment approaches. Targeted therapies have emerged as effective alternatives, potentially reducing long-term toxicities. Future research should focus on optimizing therapy sequences, understanding long-term impacts, and ensuring global accessibility to advanced treatments.

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Gastrointestinal malignancies are one of the major worldwide health concerns. In the present review, we have assessed the plausible therapeutic implication of Ursolic Acid (UA) against gastrointestinal cancer. By modulating several signaling pathways critical in cancer development, UA could offer anti-inflammatory, anti-proliferative, and anti-metastatic properties. However, being of low oral bioavailability and poor permeability, its clinical value is restricted. To deliver and protect the drug, liposomes and polymer micelles are two UA nanoformulations that can effectively increase medicine stability. The use of UA for treating cancers is safe and appropriate with low toxicity characteristics and a predictable pharmacokinetic profile. Although the bioavailability of UA is limited, its nanoformulations could emerge as an alternative to enhance its efficacy in treating GI cancers. Further optimization and validation in the clinical trials are necessary. The combination of molecular profiling with nanoparticle-based drug delivery technologies holds the potential for bringing UA to maximum efficacy, looking for good prospects with GI cancer treatment.

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Exosomes are extracellular vesicles well known for facilitating cell-to-cell communication by distributing essential macromolecules like proteins, DNA, mRNA, lipids, and miRNA. These vesicles are abundant in fluids distributed throughout the body, including urine, blood, saliva, and even bile. They are important diagnostic tools for breast, lung, gastrointestinal cancers, etc. However, their application as cancer biomarkers has not yet been implemented in most parts of the world. In this review, we discuss how OMICs profiling of exosomes can be practiced by substituting traditional imaging or biopsy methods for cancer detection. Previous methods like extensive imaging and biopsy used for screening were expensive, mostly invasive, and could not easily provide early detection for various types of cancer. Exosomal biomarkers can be utilized for routine screening by simply collecting body fluids from the individual. We anticipate that the use of exosomes will be brought to light by the success of clinical trials investigating their potential to enhance cancer detection and treatment in the upcoming years.